The 1.alpha.-hydroxylated metabolites of vitamin D--most importantly 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxyvitamin D.sub.2 --are known as highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has also been established. V. Ostrem et al, Proc. Natl. Acad. Sci. USA, (1987), 84, 2610. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, various side chain fluorinated derivatives of 1.alpha.,25-dihydroxyvitamin D.sub.3, and side chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds with advantageous therapeutic activity profiles and thus numerous of these compounds are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Recently, a new class of vitamin D analogs has been discovered, i.e. the so-called 19-nor-vitamin D compounds. 19-Nor-vitamin D compounds are vitamin D analogs in which the ring A exocyclic methylene group (carbon 19) typical of all vitamin D compounds has been removed and replaced by two hydrogen atoms. Specifically, these compounds exhibit a selective activity profile with high potency in inducing cellular differentiation, and minimal bone calcification activity. Such a differential activity profile renders these compounds useful for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of these 19-nor-vitamin D analogs have been described (Perlman et al. Tetrahedron Letters 31, 1823 (1990); Perlman et al Tetrahedron Letters 32., 7663 (1991), and DeLuca et al U.S. Pat. No. 5,086,191).
In U.S. Pat. No. 4,666,634, 2.beta.-hydroxy and alkoxy analogs of 1.alpha.,25-dihydroxyvitamin D.sub.3 have been described and examined as potential drugs for osteoporosis and as antitumor agents See also T. Okano et al, Biochem. and Biophys. Res. Comm., (1989) 163, 1444. However the new analogs also have many undesired side effects most notable of which is the potential development of hypercalcemia upon administration.
In a continuing effort to explore the new 19-nor class of pharmacologically important vitamin D analogs, the 2.alpha.- and 2.beta.-hydroxy as well as the 2.alpha.(3'-hydroxypropoxy)- and the 2.beta.(3'-hydroxypropoxy)- and 2.alpha.(benzyloxy)-analogs of 19-nor-1.alpha.,25-dihydroxyvitamin D.sub.3 have now been synthesized. The two 2-hydroxy analogs showed in vivo calcium transport with little or no bone calcium mobilization; the 2.beta.- more than the 2.alpha.- analog. Both 2-hydroxy analogs induced differentiation of malignant cells. These two analogs thus show promise in the treatment of osteoporosis. The 2.alpha.-hydroxypropoxy analog showed a selective activity profile, combining high potency in inducing differentiation of malignant cells with very low bone calcium mobilizing activity, a possible use in the treatment of cancer.